[unreadable] No approved therapy can prevent the progressive neurodegeneration of Alzheimer's disease (AD). Accumulation of the neurotoxic amyloid-beta (A-beta) peptide is thought to be pathogenic, though underlying mechanisms are incompletely understood. Studies in cell lines suggest A-beta binds to the p75 neurotrophin receptor to activate deleterious signals and induce cell death. Our laboratory identified novel, nonpeptide small molecule ligands of the p75 neurotrophin receptor, C24 and C31, which bind to p75 and activate survival promoting signaling, and which protect primary neurons from A-beta-induced degeneration. If A-beta toxicity in neurons is mediated, in part, by p75, C24 and C31 could inhibit this interaction. Alternatively, survival signaling activated by C24 and C31 could downregulate deleterious A-beta signaling to prevent degeneration. We will determine the role of p75 in A-beta induced degeneration, using p75 -/- neurons, in vitro and in vivo. In addition, we will determine whether C24 and C31 inhibit deleterious A-beta signaling and degeneration, in vitro and [in transgenic mouse models of AD]. This will contribute to understanding AD pathogenesis and to the development of improved therapeutic strategies. [unreadable] [unreadable] [unreadable]